ABCMdb

ABCB1 p.Arg467Lys

Predicted by SNAP2:	A: D (85%), C: D (85%), D: D (95%), E: D (95%), F: D (91%), G: D (91%), H: D (85%), I: D (91%), K: D (91%), L: D (91%), M: D (91%), N: D (91%), P: D (95%), Q: D (85%), S: D (91%), T: D (85%), V: D (91%), W: D (95%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Molecular aspects of fluconazole resistance develo... Mycoses. 1999;42(7-8):453-8. Franz R, Ruhnke M, Morschhauser J
Molecular aspects of fluconazole resistance development in Candida albicans.
Mycoses. 1999;42(7-8):453-8., [PMID:10546486]

Abstract [show]
Serial Candida albicans isolates from recurrent episodes of oropharyngeal candidosis (OPC) in four AIDS patients which became fluconazole-resistant during therapy were analysed by molecular methods. The CARE-2 fingerprint patterns of the isolates demonstrated that in all four patients fluconazole resistance developed in a previously more susceptible strain. In two cases resistance correlated with enhanced expression of genes encoding multiple drug resistance proteins that mediate active drug efflux. Enhanced mRNA levels of the CDR1/CDR2 genes encoding ABC transporters were observed in fluconazole-resistant isolates from one patient compared with the corresponding susceptible isolates. The fluconazole-resistant isolates from another patient exhibited high mRNA levels of the MDR1 gene encoding a membrane transport protein of the major facilitator superfamily that was not detectably expressed in any of the fluconazole-susceptible isolates. These results demonstrate that in AIDS patients with recurrent OPC the development of fluconazole resistance is usually caused by molecular changes in a previously susceptible C. albicans strain from the same patient.

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137 Microbiology 143, 17 White, T. C. (1997) The presence of an R467K amino405-416. Login to comment

[hide] Drug resistance genes and trailing growth in Candi... J Antimicrob Chemother. 2004 Feb;53(2):217-24. Epub 2003 Dec 19. Lee MK, Williams LE, Warnock DW, Arthington-Skaggs BA
Drug resistance genes and trailing growth in Candida albicans isolates.
J Antimicrob Chemother. 2004 Feb;53(2):217-24. Epub 2003 Dec 19., [PMID:14688046]

Abstract [show]
OBJECTIVES: To investigate possible molecular mechanisms of azole resistance among fluconazole-susceptible bloodstream isolates of Candida albicans that displayed the trailing growth phenomenon, and to compare these isolates with bloodstream and mucosal isolates that showed reduced susceptibilities to fluconazole. METHODS: Twelve C. albicans isolates-seven trailing and five susceptible dose dependent (SDD) or resistant (R)-were screened for ERG11 mutations by DNA sequencing and quantification of ERG11, CDR1 and MDR1 expression by RT-PCR using the LightCycler high-speed PCR system. RESULTS: SDD and R isolates possessed more homozygous ERG11 mutations than did the trailing isolates. Two of these, V404I and V509M, have not been described previously and were found exclusively in fluconazole SDD and R isolates. Quantification of ERG11 expression revealed that both trailing and SDD and R isolates were capable of ERG11 up-regulation in response to fluconazole, although the SDD and R isolates showed maximal up-regulation at higher fluconazole concentrations. Quantification of CDR1 and MDR1 revealed that all isolates, regardless of in vitro fluconazole response, were capable of CDR1 and MDR1 up-regulation following fluconazole exposure. Furthermore, the SDD and R isolates expressed higher constitutive levels of CDR1 and MDR1 or CDR1, respectively, in the absence of drug compared with trailing isolates. CONCLUSIONS: Trailing isolates, although susceptible to fluconazole, express the same molecular mechanisms as SDD and R isolates following fluconazole exposure but regulate them differently.

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220 Five of these, K143R, V404I, F449V, R467K and V509M, were found exclusively in non-trailing isolates with reduced fluconazole susceptibilities (isolates 8-12), andall were due tohomozygous nucleotide substitutions. Login to comment
265 1 2 3 4 5 6 7 8 9 10 11 12 Amino acid substitutiona Reference nucleotideb Nucleotide substitutionc F 105 F T T/C C T/C C T/C T/C D 116 E T T/A A T/A T/A T/A K 119 K A A/G G A/G A/G A/G K 128 T A A/C A/C S 137 S C C/T T C/T T T C/T C/T C/T K 143 R A G H 183 H T T/C C C C L 220 L C C/T T T T T C/T T T E 266 D A C A/C C L 320 L G A V 332 V T T/C C C C C L 340 L A A/G G A/G A/G G K 342 K A A/G G S 361 S A G G L 370 L C C/T T T T T T C/T T T T F 380 F T C C Y 401 Y T C C C C C V 404 I G A P 419 P T C C D 428 D T C C V 437 I G A A G 448 G G G/T A F 449 V T G V 452 V T C V 456 V T A R 467 K G A L 480 L A A/G G G G G G A/G G G N 490 N T T/C C C C C T/C C C V 509 M G A T229A, S279F, K287R, G307S, S405F, G448E, G448R, F449L, V452A, G464S, G465S, R467K and I471T.13,16,17,24 In this study, we found two of these mutations (K143R and R467K) in fluconazole-resistant C. albicans isolates derived from cases of oropharyngeal candidiasis (isolates 11 and 12). Login to comment

[hide] Mechanisms of azole resistance in a clinical isola... Antimicrob Agents Chemother. 2005 Nov;49(11):4608-15. Vandeputte P, Larcher G, Berges T, Renier G, Chabasse D, Bouchara JP
Mechanisms of azole resistance in a clinical isolate of Candida tropicalis.
Antimicrob Agents Chemother. 2005 Nov;49(11):4608-15., [PMID:16251302]

Abstract [show]
Azole resistance has been insufficiently investigated in the yeast Candida tropicalis. Here we determined the molecular mechanisms responsible for azole resistance in a clinical isolate of this pathogenic yeast. Antifungal susceptibility testing performed by a disk diffusion method showed resistance or markedly decreased susceptibility to azoles, which was confirmed by determination of MICs. Considering the relationship between azole susceptibility and the respiration reported for other yeast species, the respiratory activity of this isolate was investigated. Flow cytometry using rhodamine 123 and oxygraphy demonstrated an increased respiratory activity, which was not linked to an overexpression or increased number of copies of the mitochondrial genome. Among previously described resistance mechanisms, an increased activity of efflux pumps was investigated by flow cytometry using rhodamine 6G. However, the efflux of rhodamine 6G was lower in the resistant isolate than in susceptible ones. Likewise, real-time reverse transcription-PCR quantification of the expression of C. tropicalis MDR1 (CtMDR1), which encodes an efflux protein belonging to the major facilitator superfamily, did not show overexpression of this gene. In contrast, the resistant isolate overexpressed the CtERG11 gene coding for lanosterol 14alpha-demethylase. This was in agreement with the larger amount of ergosterol found in this isolate. Moreover, sequencing of CtERG11 showed a point mutation leading to a tyrosine substitution in the protein sequence, which might lead to decreased binding affinity for azoles. In conclusion, overexpression of CtERG11 associated with a missense mutation in this gene seemed to be responsible for the acquired azole resistance of this clinical isolate.

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230 At least 12 have been reported to occur in azole-resistant clinical isolates of C. albicans and 7 in C. glabrata, and the mutations most frequently associated with azole resistance were Y132H, D278E, S405F, G464S, and R467K. Login to comment

[hide] Mutations in the multi-drug resistance regulator M... Mol Microbiol. 2008 Aug;69(4):827-40. Epub 2008 May 27. Dunkel N, Blass J, Rogers PD, Morschhauser J
Mutations in the multi-drug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains.
Mol Microbiol. 2008 Aug;69(4):827-40. Epub 2008 May 27., [PMID:18577180]

Abstract [show]
Overexpression of the MDR1 gene, encoding a multi-drug efflux pump of the major facilitator superfamily, is a major cause of resistance to the widely used antifungal agent fluconazole and other toxic substances in the fungal pathogen Candida albicans. We found that all tested clinical and in vitro generated C. albicans strains that had become fluconazole-resistant by constitutive MDR1 upregulation contained mutations in the MRR1 gene, which encodes a transcription factor that controls MDR1 expression. Introduction of the mutated alleles into a drug-susceptible C. albicans strain resulted in activation of the MDR1 promoter and multi-drug resistance, confirming that the amino acid substitutions in Mrr1p were gain-of-function mutations that rendered the transcription factor constitutively active. The majority of the MDR1 overexpressing strains had become homozygous for the mutated MRR1 alleles, demonstrating that the increased resistance level conferred by two gain-of-function alleles provides sufficient advantage to select for the loss of heterozygosity in the presence of fluconazole both in vitro and within the human host during therapy. Loss of heterozygosity usually occurred by mitotic recombination between the two chromosome 3 homologues on which MRR1 is located, but evidence for complete loss of one chromosome and duplication of the chromosome containing the mutated MRR1 allele was also obtained in two in vitro generated fluconazole-resistant strains. These results demonstrate that gain-of-function mutations in MRR1 are the major, if not the sole, mechanism of MDR1 overexpression in fluconazole-resistant strains and that this transcription factor plays a central role in the development of drug resistance in C. albicans.

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186 It was previously shown that DSY292 has acquired a Y132H mutation in one ERG11 allele, in addition to the G464S and R467K mutations that were already present in both ERG11 alleles of the matched isolate DSY291 (Sanglard et al., 1998). Login to comment

[hide] Overexpression of CDR1 and CDR2 genes plays an imp... J Int Med Res. 2010 Mar-Apr;38(2):536-45. Chen LM, Xu YH, Zhou CL, Zhao J, Li CY, Wang R
Overexpression of CDR1 and CDR2 genes plays an important role in fluconazole resistance in Candida albicans with G487T and T916C mutations.
J Int Med Res. 2010 Mar-Apr;38(2):536-45., [PMID:20515567]

Abstract [show]
This study was designed to investigate potential resistance mechanisms by studying the expression of resistant genes in 14 fluconazole-resistant Candida albicans isolates, with G487T and T916C mutations in the 14alpha-demethylase (ERG11) gene, collected from human immunodeficiency virus uninfected patients and a fluconazole-susceptible control strain. The in vitro susceptibilities of the C. albicans isolates to fluconazole were determined using the broth microdilution method and a disc diffusion assay. Expression of Candida drug resistance (CDR)1, CDR2, ERG11, fluconazole resistance (FLU)1 and multidrug resistance (MDR)1 genes was measured using real-time reverse transcription-polymerase chain reaction and evaluated relative to the expression of the control gene 18SrRNA. The CDR1 and CDR2 genes were upregulated in all the fluconazole-resistant C. albicans isolates, whereas only a few isolates showed high expression of MDR1, FLU1 and ERG11 genes compared with the control strain. In conclusion, overexpression of the CDR1 and CDR2 genes may play an important role in fluconazole-resistant C. albicans with G487T and T916C mutations.

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62 The Erg11p Y132H, T315A, S405F, G464S, R467K and I471T mutations have all been shown to be associated with azole resistance.22 - 25 Some researchers have demonstrated the structural importance of the Y118 amino acid residue in maintaining C. albicans cytochrome P450 14α-sterol demethylase P450 (CACYP51) activity and determining azole susceptibility.26 The contributions of other mutations such as Y79C, D81G, F126L and V130I to fluconazole resistance are still uncertain. Login to comment
141 25 Lamb DC, Kelly DE, White TC, et al: The R467K amino acid substitution in Candida albicans sterol 14α-demethylase causes drug resistance through reduced affinity. Login to comment

[hide] Voriconazole-induced inhibition of the fungicidal ... Antimicrob Agents Chemother. 2011 Apr;55(4):1629-37. Epub 2011 Jan 31. Lignell A, Lowdin E, Cars O, Sanglard D, Sjolin J
Voriconazole-induced inhibition of the fungicidal activity of amphotericin B in Candida strains with reduced susceptibility to voriconazole: an effect not predicted by the MIC value alone.
Antimicrob Agents Chemother. 2011 Apr;55(4):1629-37. Epub 2011 Jan 31., [PMID:21282443]

Abstract [show]
An antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in Candida albicans strains susceptible to voriconazole. Because treatment failure and the need to switch to other antifungals are expected to occur more often in infections that are caused by resistant strains, it was of interest to study whether the antagonistic effect was still seen in Candida strains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole-resistant strains, C. albicans strains with characterized mechanisms of resistance against voriconazole, as well as Candida glabrata and Candida krusei strains with differences in their degrees of susceptibility to voriconazole were exposed to voriconazole or amphotericin B alone, to both drugs simultaneously, or to voriconazole followed by amphotericin B in an in vitro kinetic model. Amphotericin B administered alone or simultaneously with voriconazole resulted in fungicidal activity. When amphotericin B was administered after voriconazole, its activity was reduced (median reduction, 61%; range, 9 to 94%). Levels of voriconazole-dependent inhibition of amphotericin B activity differed significantly among the strains but were not correlated with the MIC values (correlation coefficient, -0.19; P = 0.65). Inhibition was found in C. albicans strains with increases in CDR1 and CDR2 expression but not in the strain with an increase in MDR1 expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole-resistant Candida strains. The degree of interaction could not be predicted by the MIC value alone.

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83 Summary of drug MICs and mechanisms of resistance to voriconazole for the Candida strains Candida species and strain Name in this study MIC (mg/liter) of: Voriconazole resistance mechanisms Voriconazole Amphotericin B C. albicans C26 CA1MIC8 8 0.5 Increase in CDR1 and CDR2 mRNAs; mutations of ERG11: S405F and Y132H (26) C. albicans C40 CA2MIC8 8 0.5 Increase in MDR1 mRNA; mutations of ERG11: G464S, R467K, and Y132H (26) C. albicans C56 CA3MIC2 2 0.5 Increase in CDR1 and CDR2 mRNAs; mutations of ERG11: G129A and G464S (26) C. albicans 20288.030 CA4MIC256 256 0.5 Increase in CDR1 mRNA; upregulation of ERG11 C. glabrata B346 4018 CG1MIC0.5 0.5 0.5 NAa C. glabrata 263 SMI CG2MIC4 4 0.5 NA C. krusei B336 4026 CK1MIC0.5 0.5 0.5-1 NA C. krusei 20550.054 CK2MIC4 4 0.5 NA C. albicans CCUG 32723 CA5MIC0.004 0.004 0.25 None (voriconazole-susceptible strain included as a quality control) a NA, not analyzed. Login to comment

[hide] Multiple molecular mechanisms contribute to a step... Antimicrob Agents Chemother. 1998 Dec;42(12):3065-72. Franz R, Kelly SL, Lamb DC, Kelly DE, Ruhnke M, Morschhauser J
Multiple molecular mechanisms contribute to a stepwise development of fluconazole resistance in clinical Candida albicans strains.
Antimicrob Agents Chemother. 1998 Dec;42(12):3065-72., [PMID:9835492]

Abstract [show]
From each of two AIDS patients with oropharyngeal candidiasis, five Candida albicans isolates from recurrent episodes of infection which became gradually resistant against fluconazole during antimycotic treatment were analyzed for molecular changes responsible for drug resistance. In both patients, a single C. albicans strain was responsible for the recurrent infections, but the CARE-2 fingerprint pattern of the isolates exhibited minor genetic alterations, indicating that microevolution of the strains took place during fluconazole therapy. In the isolates from patient 1, enhanced mRNA levels of the MDR1 gene, encoding a multiple drug resistance protein from the superfamily of major facilitators, and constitutive high expression of the ERG11 gene, coding for the drug target enzyme sterol 14alpha-demethylase, correlated with a stepwise development of fluconazole resistance. The resistant strains exhibited reduced accumulation of fluconazole and, for the last in the series, a slight increase in drug needed to inhibit sterol 14alpha-demethylation in vitro. In the isolates from patient 2, increased MDR1 mRNA levels and the change from heterozygosity to homozygosity for a mutant form of the ERG11 gene correlated with continuously decreased drug susceptibility. In this series, reduced drug accumulation and increased resistance in the target enzyme activity, sterol 14alpha-demethylase, were observed. These results demonstrate that different molecular mechanisms contribute to a gradual development of fluconazole resistance in C. albicans.

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198 In that case, an R467K amino acid substitution was found in both ERG11 alleles from the isolate with elevated resistance which was not present in the previous isolates and must therefore have occurred in an intermediate isolate not recovered from the patient. Login to comment
200 The G464S mutation, which is located in the heme binding domain of the Erg11p protein near the R467K substitution described by White (38), must have been introduced into one ERG11 allele before conversion to homozygosity. Login to comment

[hide] The genetic basis of fluconazole resistance develo... Biochim Biophys Acta. 2002 Jul 18;1587(2-3):240-8. Morschhauser J
The genetic basis of fluconazole resistance development in Candida albicans.
Biochim Biophys Acta. 2002 Jul 18;1587(2-3):240-8., [PMID:12084466]

Abstract [show]
Infections by the opportunistic fungal pathogen Candida albicans are widely treated with the antifungal agent fluconazole that inhibits the biosynthesis of ergosterol, the major sterol in the fungal plasma membrane. The emergence of fluconazole-resistant C. albicans strains is a significant problem after long-term treatment of recurrent oropharyngeal candidiasis (OPC) in acquired immunodeficiency syndrome (AIDS) patients. Resistance can be caused by alterations in sterol biosynthesis, by mutations in the drug target enzyme, sterol 14alpha-demethylase (14DM), which lower its affinity for fluconazole, by increased expression of the ERG11 gene encoding 14DM, or by overexpression of genes coding for membrane transport proteins of the ABC transporter (CDR1/CDR2) or the major facilitator (MDR1) superfamilies. Different mechanisms are frequently combined to result in a stepwise development of fluconazole resistance over time. The MDR1 gene is not or barely transcribed during growth in vitro in fluconazole-susceptible C. albicans strains, but overexpressed in many fluconazole-resistant clinical isolates, resulting in reduced intracellular fluconazole accumulation. The activation of the gene in resistant isolates is caused by mutations in as yet unknown trans-regulatory factors, and the resulting constitutive high level of MDR1 expression causes resistance to other toxic compounds in addition to fluconazole. Disruption of both alleles of the MDR1 gene in resistant C. albicans isolates abolishes their resistance to these drugs, providing genetic evidence that MDR1 mediates multidrug resistance in C. albicans.

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55 An R467K mutation was detected in both ERG11 alleles of a fluconazole-resistant C. albicans isolate as compared with matched isolates from the same patient with higher sensitivity [20]. Login to comment
61 The amino acid exchanges G129A, Y132H, S405F, G464S and R467K were shown to cause fluconazole resistance by this approach [22]. Login to comment
65 The affinity for fluconazole of 14DM containing the mutations Y132H, G464S or R467K was reduced as compared with the wild-type enzyme, confirming that these naturally occurring mutations indeed caused drug resistance in clinical C. albicans isolates [25-27]. Login to comment
71 Such a change was found for clinical isolates with the G464S or the R467K mutations [20,21]. Login to comment
72 Genetic evidence suggests that a cell with two copies of R467K is significantly more resistant than a cell in which only one allele has the mutation [4]. Login to comment
75 Table 1 provides a list of Table 1 ERG11 mutations causing fluconazole resistance in clinical C. albicans strains Mutation Evidence for contribution to fluconazole resistance Reference A B C D F126L + [24] G129A + + a [22] T229A + + [24] Y132H + + + [22,23,25] G307S + + [24] S405F + + [22] F449S + [24] G464S + + + + [21,22,24,26] R467K + + + + [20,22,27] I471T + [23] A: Mutation found in a fluconazole-resistant isolate but not in a matched susceptible isolate from the same patient. Login to comment
121 For example, White [30] described gradual increases in fluconazole resistance in serial isolates of a C. albicans strain by overexpression of MDR1, ERG11, and one or more of the CDR genes, combined with the aquisition of the R467K mutation in ERG11. Login to comment

[hide] In vitro antifungal activity of BMS-207147 and itr... Diagn Microbiol Infect Dis. 1999 Oct;35(2):163-7. Fung-Tomc JC, White TC, Minassian B, Huczko E, Bonner DP
In vitro antifungal activity of BMS-207147 and itraconazole against yeast strains that are non-susceptible to fluconazole.
Diagn Microbiol Infect Dis. 1999 Oct;35(2):163-7., [PMID:10579098]

Abstract [show]
The activities of itraconazole and the new triazole BMS-207147 were determined against Candida strains that were susceptible-dose dependent (fluconazole MICs 16 to 32 micrograms/mL) or resistant (MICs > or = 64 micrograms/mL) to fluconazole. These strains included clinical isolates of Candida krusei, Candida glabrata, and Candida albicans. In addition, 16 isogenic, genetically characterized isolates of C. albicans, with progressively decreased susceptibility to fluconazole, were tested. BMS-207147 MICs to C. krusei, a species considered intrinsically resistant to fluconazole, were at 0.13 to 0.5 microgram/mL. The population distribution of the fluconazole-nonsusceptible C. glabrata was bimodal with BMS-207147/itraconazole MICs at 0.5 to 2 micrograms/mL and > or = 16 micrograms/mL. The BMS-207147 MICs to the majority of fluconazole-nonsusceptible C. albicans strains tested were < or = 1 microgram/mL. The activity of BMS-207147 was minimally affected by overexpression of the gene encoding the efflux pump MDR1, but MIC increases were observed with changes in ERG11 and with overexpression of the CDR transporter gene. Nonetheless, BMS-207147 can be active against C. albicans mutants containing cumulative resistance mechanisms to azoles. In other words, fluconazole-resistant candidal strains may be susceptible to BMS-207147.

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39 ERG11 mRNA levels increased four- to five-fold starting at isolate 13, and a single amino acid substitution (R467K) occurred in ERG11 at isolate 13 (White 1997b). Login to comment
37 ERG11 mRNA levels increased four- to fivefold starting at isolate 13, and a single amino acid substitution (R467K) occurred in ERG11 at isolate 13 (White 1997b). Login to comment

[hide] An update on antifungal targets and mechanisms of ... Med Mycol. 2005 Jun;43(4):285-318. Akins RA
An update on antifungal targets and mechanisms of resistance in Candida albicans.
Med Mycol. 2005 Jun;43(4):285-318., [PMID:16110776]

Abstract [show]
Much progress has been made in the last decade in identifying genes responsible for antifungal resistance in Candida albicans. Attention has focused on five major C. albicans genes: ABC transporter genes CDR1 and CDR2, major facilitator efflux gene MDR1, and ergosterol biosynthesis genes ERG11 and ERG3. Resistance involves mutations in 14C-lanosterol demethylase, targeted by fluconazole (FLZ) and encoded by ERG11, and mutations that up-regulate efflux genes that probably efflux the antifungals. Mutations that affect ERG3 mutations have been understudied as mechanism resistance among clinical isolates. In vitro resistance in clinical isolates typically involves step-wise mutations affecting more than one of these genes, and often unidentified genes. Different approaches are needed to identify these other genes. Very little is understood about reversible adaptive resistance of C. albicans despite its potential clinical significance; most clinical failures to control infections other than oropharyngeal candidiasis (OPC) occur with in vitro susceptible strains. Tolerance of C. albicans to azoles has been attributed to the calcineurin stress-response pathway, offering new potential targets for next generation antifungals. Recent studies have identified genes that regulate CDR1 or ERG genes. The focus of this review is C. albicans, although information on Saccharomyces cerevisiae or Candida glabrata is provided in areas in where Candida research is underdeveloped. With the completion of the C. albicans genomic sequence, and new methods for high throughput gene overexpression and disruption, rapid progress towards understanding the regulation of resistance, novel resistance mechanisms, and adaptive resistance is expected in the near future.

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40 Strong evidence for another four mutants was provided by showing reduced susceptibilities of demethylase activity from clinical resistant Table 1 Mutations in ERG11 that confer FLZ resistance, and their methods of determination Mutation Effect Method(s) Ref Y132H(F) Altered FLZ binding, no reduction in activity; resistant transformants SDM, confers SDD, confers R in combination with S405F; SDM-EA;/Ca(Sc) confers R growth in combination with G450E; combinations may confer R to posaconazole [11,284,285] T315A Altered FLZ binding, altered heme binding, reduced activity; resistant transformants SDM confers R; SDM-EA [286] R467K Altered heme, reduced FLZ binding; resistant transformants SDM confers SDD; confers R in combination with G464S; SDM-EA [18,287,288] G464S Altered heme, reduced FLZ binding, reduced activity; resistant transformants SDM-EA; /Ca(Sc) confers SDD, confers increased SDD in combination with G129A (a susceptible polymorphism), confers R in combination with R467K, may confer R to posaconazole in combination with G307S [18,289/291] A61V Resistant clinical strain with other mutations, resistant transformants /Ca(Sc) confers SDD growth [291] K143E/ T229A Found together in resistant isolates, resistant enzyme, resistant transformants /Ca(Sc) confers SDD growth; EA [12,291,292] S405F Found in resistant isolates, unique mutation in some, also found in sensitive isolates in combination with other mutations, resistant transformants /Ca(Sc) confers SDD; confers R in combination with Y132H [12,18] G450E Found with other mutations in many resistant strains, resistant enzyme; resistant transformants /Ca(Sc) confers R growth in combination with Y132H; EA [12,291,292] F72L Found in one resistant strain with other mutations, resistant enzyme EA [292] F126L Found in one strain with other mutations, resistant enzyme EA [292] E266D Found with other mutations in many resistant strains, resistant enzyme EA [12,292] F449L Found in strains with other mutations, resistant enzyme EA [12,292] F105L Found in resistant isolates, unique ERG11 mutation in some Correlative, located in substrate access channel in model [12,290] Abbreviations: SDD/susceptible, dose-dependent (resistant in vitro to 8/32 mg/ml FLZ); R: resistant in vitro to 64/mg/ml FLZ). Login to comment

[hide] [Characterization of azole resistance mechanisms i... Rev Chilena Infectol. 2014 Oct;31(5):511-7. doi: 10.4067/S0716-10182014000500001. Fuentes M, Hermosilla G, Alburquenque C, Falconer MA, Amaro J, Tapia C
[Characterization of azole resistance mechanisms in Chilean clinical isolates of Candida albicans].
Rev Chilena Infectol. 2014 Oct;31(5):511-7. doi: 10.4067/S0716-10182014000500001., [PMID:25491448]

Abstract [show]
INTRODUCTION: The commensal yeast Candida albicans, can cause superficial or systemic candidiasis in susceptible hosts. In Chile, azole antifungals are the most widely used drugs in the treatment of candidiasis. In a previous study performed at our center, 2.1 and 1.6% of clinical isolates of C. albicans were found to be resistant to fluconazole and voriconazole, respectively. OBJECTIVE: To characterize the resistance mechanisms involved in azoles resistance in Chilean clinical isolates. METHODOLOGY: Eight resistant, nine susceptible-dose dependent (SDD) and 10 susceptible strains (n: 27) were selected according to the Clinical Laboratory Standards Institute (CLSI) M27-S3 criteria, from vaginal and urine samples. Mutations in the 408-488 region of the ERG11 gene were studied by sequencing, and the relative expression of ERG11 gene and efflux pump genes CDR1, CDR2 and MDR1, was evaluated by quantitative real-time PCR (q-PCR). RESULTS: No mutations were detected in the ERG11 gene and its overexpression was found only in 12.5% of the resistant strains (1/8). The most prevalent mechanism of resistance was the over-expression of efflux pumps (62.5%; 5/8). CONCLUSION: The study of the expression of efflux pumps by q-PCR could be a useful diagnostic tool for early detection of azole resistance in C. albicans.

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24 Anivel molecular, diversos mecanismos de resistencia a azoles han sido descritos en C. albicans, como mutaciones puntuales en la regi&#f3;n 405-488 del gen que codifica para la enzima "blanco" del f&#e1;rmaco ERG11, como por ejemplo G464S, R467K y I471T, y/o sobre-expresi&#f3;n de este gen21-23 . Login to comment